Pharma Treasures: FDA INSPECTION AND ENFORCEMENT ACTIONS

FDA INSPECTION AND ENFORCEMENT ACTIONS

FDA 483’s - (Notice of inspectional observations)

483 is a form issued by an FDA investigator to a company at the conclusion of a GMP, GCP or GLP inspection (or any inspection) setting forth the observations the FDA employee finds objectionable, and considers to be possible violations of the law.

They are inspectional observations, and do not represent a final Agency determination regarding firms compliance.” The FDA-483 can be amended after an inspection by the investigator who issued it and re-issued.Objective of form 483 is to fix the problem areas and bring the firm in to compliance.

The FDA Form 483 is a report which does not include observations of questionable or unknown significance at the time of the inspection. There may be other objectionable conditions that exist at the firm that are not cited on the FDA Form 483. FDA investigators are instructed to note only what they saw during the course of the inspection. Companies are responsible to take corrective action to address the cited objectionable conditions and any related non-cited objectionable conditions that might exist.

The FDA established a policy concerning written responses to FDA-483 observations. The policy gives companies 15 days to respond in writing to the FDA after a 483 is issued, if they wish their comments to be taken into consideration when the FDA is deciding whether or not to issue a warning letter.

Companies are not required to reply at all, but nearly everyone does, and it is expected. Failure to respond is unusual, and could be taken as a sign of indifference by the FDA. A prompt, proper response is essential to avoid further action by the FDA. In fact, the vast majority of 483s do not lead to warning letters. Warning letters are sent when the FDA feels the observations made during the inspection are significant, and a stronger warning than the 483 itself is warranted.

FDA 483 lists only significant observations. Observations of lesser significance will be included in narrative report (EIR).

EIR - (Establishment inspection Report)

After departing, the FDA inspector(s) prepare a detailed ‘Establishment Inspection Report (EIR)’ .This should be done in 30 working dates. The EIR becomes FDA’s primary comprehensive record of inspector’s visit to the firm, and it may be reviewed by FDA compliance officers looking for violations of law. EIR’s are subject to release under the freedom of information act (FOI) to any member of public, including competitors.EIR includes

Ø Brief history of prior inspectional findings, including any action taken by FDA or corrective action taken by the firm in response to a previous inspection.

Ø The investigator’s narrative report.

Ø Any refusals, voluntary corrections, or promises made by the firm’s management.

Ø Copies of forms the FDA issued to the firm during the inspection, including the FDA Form 483.

Warning Letters

The Warning Letter is a document that usually originates from the FDA-483 observations (a critical 483 observation may leads to a warning letter) that have been linked to citations by one or more legal reviews within the Compliance and legal branch of the FDA. A Warning Letter is informal and advisory. It communicates the agency's position on a matter, but it does not commit FDA to taking enforcement action. For these reasons, FDA does not consider Warning Letters to be final agency action on which it can be sued. The Warning Letter is issued by the agency and not the investigator.

The warning letter generally represents FDA's first official notification to a firm or individual that FDA has found that one or more products, practices, processes, or other activities are in violation of the Food, Drug, and Cosmetic Act. The warning letter affords firms the opportunity to voluntarily take corrective action prior to the initiation of formal enforcement action. The company must respond within 15 days and explained in detail how to resolve the deficiencies on the one hand and how a recurrence can be prevented on the other hand.

There are two purposes: (1) obtain prompt, voluntary correction of the issues cited by the FDA and (2) establish a background of prior warning so that if the FDA has to seek court intervention, they can show that they exhausted their administrative options before asking the court to intervene through formal litigation.

The primary consequences of a warning letter are the publicity (since warning letters are posted on FDA’s web site), and the time and expense to take the necessary corrective actions, and deal with the FDA.

FDA Enforcement Actions

As an outcome of noncompliance, following unpleasant events can happen.

1.Influence on product approval:

Temporary Denial of Approval: FDA can withhold approvals of generic drug applications if the firm is under active criminal investigation for dishonest conduct involving its drug applications (for example, bribery or material misrepresentations).
Withdrawal of Approval: For a generic drug that's already been approved, FDA may withdraw that approval if the company used bribery or fraud to get approval or if the company can't produce the drug properly.

2.FDA Import Alert:

The company's product (or products) may no longer be imported into the United States. The goods remain at customs. An import alert allows FDA to detain, without physically examining; products that either have or potentially could violate the Food, Drug, and Cosmetic Act.

3.Debarment of Individuals and Firms:

Permissive Debarment of Individuals: FDA has the option to debar, for up to five years, individuals convicted of certain crimes, described in the act, that are related to the regulation of drugs but do not require mandatory debarment. In January 1997, FDA used this authority for the first time, debarring the head of a blood plasma facility convicted of falsifying blood records.

Debarment of Firms: Firms are also subject to mandatory or permissive debarment. They can be prohibited from submitting applications for generic drug approval (in this case, the law lives up to its name and only applies to generics) for certain crimes relating to the development or approval of generic drug applications. They can be debarred for up to 10 years, depending on the seriousness of the crime and other factors, and they can be debarred permanently if they are convicted a second time while debarred.

4.Civil Penalties:

Besides fines for violating a debarment, fines of up to $1 million may also be imposed on a company for bribery, false statements, or other wrongful conduct involving a generic drug application.

5.Suspension of Distribution:

FDA can suspend marketing of some or all of a company's drug products if the company is under investigation for certain conduct that may influence the safety or effectiveness of a drug.

Reference

• Investigators Operations Manual

– http://www.fda.gov/ora/inspect_ref/iom/iomoradir.html

• Regulatory Procedures Manual

– http://www.fda.gov/ora/compliance_ref/rpm/default.htm